Type 2 diabetes (T2D) is a growing health problem, especially in minority race-ethnic groups. Ancestral variation in genetic background coupled with recent, rapid increases in obesity and unhealthy behavioral and social factors account for rising rates of T2D and its disparities in the U.S. The proposed research focuses on prediabetes, where intervention is known to prevent T2D, and where downstream race-ethnic disparities in T2D are suspected to begin. Phenotypic race-ethnic differences in prediabetes have been characterized, but genetic differences have not. There are strong scientific as well as ethical reasons to study race-ethnic differences in T2D genetic risk. This is a renewal of a mid-career investigator award in patient-oriented research (K24). The candidate, James B. Meigs MD MPH, has devoted his patient-oriented research career to study of the cause and prevention of type 2 diabetes. This award will support the following Specific Aims: 1. Discover, map, and characterize T2D quantitative trait-associated genetic loci in multi-ethnic population samples (African American, Hispanic, Asian and European ancestry). This will be achieved using staged genome-wide association studies with meta-analysis and with characterization of confirmed T2D quantitative trait loci using interaction, outcomes, physiology, pathway, and sequencing studies. Diabetes-related quantitative traits include levels of fasting insulin, glucose, and hemoglobin A1c; 2. Translate new genetic knowledge to diverse race-ethnic samples for clinical and population health benefit using longitudinal and multilevel tests of genetic measures and social, behavioral, environmental and biophysiological measures of risk for elevated fasting glucose, prediabetes, or clinical T2D; 3. Build on the candidate's successful research and mentoring program by ensuring mid-career protected time for patient-oriented research program development within the superb environment of Harvard, Massachusetts General Hospital and an extensive network of research collaborations, and by maintaining the ongoing capacity to provide mentoring to a larger number of junior patient-oriented investigators. Patient-oriented research is critical for the translation of scientific knowledge into population health benefit. T2 is a rapidly growing clinical and public health problem. This mid-career award application seeks to directly address the need for patient-oriented research and mentoring focused on the causes and consequences of T2D. Expanded knowledge of precursors of T2D is critical to identify novel approaches for prevention and control of the widening diabetes epidemic. PUBLIC HEALTH RELEVANCE: Type 2 diabetes (T2D) is a growing health problem, especially in minority race-ethnic groups. The proposed research focuses on improved knowledge of prediabetes risk factors like fasting glucose, and seeks to discover and characterize fasting glucose and related trait genetic loci in multi-ethnic population samples (African American, Hispanic, Asian and European). The research will translate new genetic knowledge for clinical and population health benefit using longitudinal and multilevel tests of genetic, social, behavioral, environmental and biophysiological measures of risk for elevated fasting glucose, prediabetes or clinical T2D.